WO2022013478A1

WO2022013478A1 - Diagnostic method and compounds for the treatment of infections caused by a pathogen

Info

Publication number: WO2022013478A1
Application number: PCT/ES2021/070528
Authority: WO
Inventors: Fernando Moreno Egea
Original assignee: Solutex Gc, S. L.
Priority date: 2020-07-17
Filing date: 2021-07-16
Publication date: 2022-01-20
Also published as: EP4183392A1; US20230273228A1

Abstract

The present invention provides a new family of compounds which are characterized as being long-chain polyunsaturated fatty acids oxidized at certain positions, and which can be used for the treatment of infections caused by a pathogen in the respiratory system. Furthermore, the present invention shows a method of diagnosing and/or monitoring these types of diseases to be treated with the compounds of the invention.

Description

DIAGNOSTIC METHOD AND COMPOUNDS FOR THE TREATMENT OF INFECTIONS CAUSED BY A PATHOGEN

The present invention provides compounds and compositions that can be administered for the treatment of infections caused by a pathogen, infectious agent, or pathogenic biological agent.

STATE OF THE ART

Pneumonia or pneumonia is a disease of the respiratory system that consists of inflammation of the alveolar spaces of the lungs. Pneumonia can be classified according to the part of the body affected, for example, an entire lung lobe (lobar pneumonia), a lobe segment, the alveoli next to the bronchi (bronchopneumonia), or the interstitial tissue (interstitial pneumonia). Pneumonia causes lung tissue to look red, swollen, inflamed, and painful. Pneumonia can be a serious disease if not detected early, and can be fatal, especially among the elderly and the immunosuppressed. In particular, AIDS patients frequently contract Pneumocystis pneumonia. People with cystic fibrosis are at high risk for pneumonia because fluid continually builds up in their lungs.

Pneumonias can also be classified based on who causes them, such as bacterial pneumonia, atypical pneumonia, and viral pneumonia.

In viral pneumonia, the viruses reach the lung through droplets or microdroplets inhaled or ingested through the nose and mouth, invading the cells lining the airways and alveoli. This invasion often leads to cell death, either directly or through apoptosis. When the immune system responds to the viral infection, the lung damage worsens. Leukocytes, mainly lymphocytes, activate a variety of chemical mediators of inflammation, such as cytokines, which increase the permeability of the bronchial alveolar wall allowing the passage of fluids. The combination of cell destruction and the passage of fluids into the alveoli impairs gas exchange. In addition to lung damage, many viruses infect other organs and can interfere with multiple functions, and causing other diseases. Viral infection can also make the host more susceptible to bacterial infection.

Among the causes of viral pneumonia are: influenza A and B viruses, respiratory syncytial virus (RSV), human parainfluenza virus, adenovirus, metapneumovirus, severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV1), coronavirus severe acute respiratory syndrome 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus 229E (HCoV-229E), coronavirus NL63 (HCoV-NL63), coronavirus OC43 (HCoV-OC43) , coronavirus HKU1 (HC0V-HKUI), and hantavirus. On the other hand, there are viruses that mainly cause other diseases, but that sometimes cause pneumonia, and which include: herpes simplex virus (HSV), varicella-zoster virus (VZV), measles virus, rubella, cytomegalovirus (CMV), mainly in people with immune system problems, smallpox virus, dengue virus. Viral pneumonia affects about 200 million people a year in the world.

Severe Acute Respiratory Syndrome (SARS) is a viral respiratory illness caused by a coronavirus, called SARS-associated coronavirus, for example, SARS-CoV1 and SARS-CoV2. SARS was first reported in Asia in 2003. Within months, SARS spread across three continents before the global outbreak could be contained. SARS usually begins with a high fever, greater than 38.0°C. Other symptoms may include a headache, a general feeling of discomfort, and body aches. Some people experience mild respiratory symptoms early in the illness. After 2 to 7 days, SARS patients may develop a dry cough, and most develop pneumonia.

The SARS-CoV-2 coronavirus is the cause of the current coronavirus infectious disease 2019 or COVID-19 pandemic and shows many similarities to SARS (fever, cough, fatigue, shortness of breath and loss of smell), evolving in severe cases to viral pneumonia, cytokine storm and multiple organ failure. The latter has been associated, among others, with disseminated intravascular coagulation, or defibrination syndrome, which is a pathological process that occurs as a result of excessive thrombin formation, and which induces the consumption of coagulation factors and platelets in the blood. , which produces the appearance of hemorrhages in different parts of the body, obstructive thrombosis (microclots) of the microcirculation, necrosis and organic dysfunctions (Tang N., et al., “Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopath, J. Thromb. Haemost., 2020; 18: 1094-9). The most concerning symptoms include shortness of breath, persistent chest pain, confusion, difficulty waking up, and bluish skin.

Currently, there is no specific treatment or vaccine for COVID-19.

As mentioned above, the cytokine storm is a dangerous syndrome that can be triggered by overstimulation of cytokines during pneumonia, or in the particular case of COVID-19. Thus, a patient who apparently evolves favorably from COVID-19 can suddenly worsen and generate severe respiratory failure due to a sudden and hypertrophied reaction of the immune system that generates large-scale pulmonary inflammation. During a cytokine storm, the immune system responds disproportionately, producing massive inflammation in the respiratory system that, in some cases, ends up generating respiratory failure and multi-organ failure.

Cytokines are proteins that regulate the function of the cells that produce them on other cell types. They are the agents responsible for a part of intercellular communication, they induce the activation of specific membrane receptors, functions of cell proliferation and differentiation, chemotaxis, growth and modulation of immunoglobulin secretion. They are mainly produced by activated lymphocytes and macrophages, although they can also be produced by polymorphonuclear leukocytes (PMN), endothelial cells, epithelial cells, adipocytes, muscle tissue (myocytes) and connective tissue. Cytokines secreted by lymphocytes are called lymphokines, those produced by macrophages (Mf) are monokines, etc. (depending on cell type). Its fundamental action consists in the regulation of the inflammation mechanism. There are pro-inflammatory and anti-inflammatory cytokines.

Each cytokine binds to a specific cell surface receptor, generating cell signaling cascades that alter cell function. This includes upregulation or downregulation of various genes and their transcription factors that result in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect through feedback regulation. The main cytokines that act in the nonspecific response or inflammation are: Interleukin 1 (IL-1), Tumor Necrosis Factor Alpha (TNF-a), Interleukin 8 (IL-8), Interleukin 12 (IL-12), Interleukin 16 (IL-16) and Interferons. All of them are proinflammatory. IL-6 and IL-12 also act in specific immunity: IL-6 is an autocrine factor of B7 lymphocytes while IL-12 stimulates cytotoxic cellular immunity.

Specialized pro-resolving mediators or SPMs (Specialized Proresolving Mediators) are lipid mediators that act in the process of resolving inflammation and, therefore, can modulate all those processes that occur with inflammation and that must be brought to homeostasis, avoiding thus its chronification. SPMs are produced by cells of the innate immune system through the enzymatic conversion of essential fatty acids such as arachidonic acid (AA), eicosapentaenoic acid (EPA), n-3 docosapentaenoic acid (DPA n-3) and docosahexaenoic acid. (DHA).

SPMs can be classified into four families: lipoxins, resolvins, protectins, and maresins. These endogenous lipid mediators share basic physiological properties in the regulation of host responses for the active improvement of the resolution of inflammatory response mechanisms, such as: the reduction of the production of proinflammatory mediators, the limitation of neutrophil trafficking, stimulation of phagocytosis of apoptotic cells of macrophages, phagocytosis of bacteria and elimination of cellular debris, through the modulation of G protein-coupled receptors (GPCR).

On the other hand, certain SPMs have been shown to have potent activity against lung infections and inflammation (Nat. Rev. Immunol. 2016, 16(1): 51-67). In addition, SPMs induce an anti-inflammatory response by inhibiting granulocyte migration, disrupting activation of sensory neurons, and dampening cytokine production by a variety of structural cells, including epithelial cells, endothelial cells, and fibroblasts. Specifically, Protectin D1 (PD1) limits the pathogenicity of influenza by directly interacting with the RNA replication machinery to inhibit nuclear export of viral RNA. In particularly virulent influenza strains, PD1 formation is insufficiently regulated, leading to more efficient viral replication and its demise.

Although it has been observed that certain SPMs have antiviral activity, the antiviral activity of the family of maresins described in the present invention has never been described.

Regarding the family of maresins, it has been proven that these compounds promote the resolution of acute inflammation (Serhan, CN et al., PCT/US2009/056998). In addition, a particular member, Maresin 1, has been shown to resolve inflammation in the lung caused by allergy (Krishnamoorthy, N. et al., J. Immunol. 2015, 194, 863-867), and reduce the response proinflammatory in the epithelial cells of the bronchi in the presence of organic dust (Nordgren, TM et al., Respir. Res. 2013, 14, 51).

For all of the above, there is a need to find drugs capable of modulating an adequate response of the organism against external aggression by a pathogen. If this type of drug can also mitigate, alleviate and even prevent the appearance of the so-called cytokine storm, then it will be more effective in the treatment of a patient affected by a disease, condition or syndrome caused by a pathogen.

In WO2018098244, Serhan CN et al., describe a diagnostic method based on the identification of sets of lipid mediators such as, for example, certain prostaglandins and/or certain SPMs, and their quantification in blood and/or in the coagulation process of the blood. Thus, a certain set of lipid mediators together with the measurement of their concentration levels could be associated with a certain disease. An association of such characteristics may make it possible to obtain a diagnostic method and/or a method for monitoring the evolution of a given disease in a patient suffering from this disease. However, the determination of one or more sets of lipid mediators that are specific to a given disease is not obvious, since to date dozens of lipid mediators have been identified (prostaglandins, thromboxanes, leukotrienes, SPMs) and they are scattered throughout the whole organism.

Obtaining a method for diagnosing and monitoring the evolution of a patient affected by a disease caused by a pathogen, which presents with pulmonary inflammation and/or a cytokine storm, such as pneumonia, viral pneumonia, or the Covid-19 will provide a very useful tool for the diagnosis, treatment and follow-up of a patient suffering from a disease of these characteristics.

DESCRIPTION OF THE INVENTION

The authors of the present invention have surprisingly found a family of compounds that are unsaturated analogs of docosanoic acid that reduce the cytokine production in lung tissue. Therefore, these compounds are useful for the treatment of infections caused by the presence of a pathogen in the respiratory system, and which are represented by the formulas: (I), (la), (Ib), (le), ( Id), (le), (II), (Na), (llb), (lie), (III), (Illa), (lllb), (lile), (llld), (IV), (IVa) , (IVb), (V), (Va), (Vb),

their pharmaceutically acceptable salts, tautomers, and/or solvates thereof; where each of Pi and P ₂ , individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)0R ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ 0R ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — 0S(0)R ^d , — 0S(0) ₂ R ^d , — 0S(0) ₂ 0R ^d , — 0S(0) ₂ NR ^c R ^c , — C(0)R ^d , — C(0)0R ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C(NOH)R ^a , — C(NOH)NR ^c R ^c , — 0C(0)R ^d , — 0C(0)0R ^d , — 0C(0 )NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c or — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; and each R ^d , independently is a protecting group or R ^a ; where Ri and R ₂ are independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (Cede)arylalkyl, benzyl, heteroalkyl 2 to 6 membered, 3 to 8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4 to 11 membered cycloheteroalkylalkyl, 5 to 10 membered heteroaryl, or 6 to 16 membered heteroarylalkyl; for use in the treatment of infections caused by the presence of a pathogen in the respiratory system.

A second inventive aspect, the present invention comprises a method for diagnosing and/or monitoring the condition of a patient suffering from an infection caused by the presence of a pathogen in the respiratory system, based on the identification of a set of pro-resolving lipid mediators in the blood of said patient, and quantification of the concentration in blood, serum and/or plasma of said lipid mediators. In certain cases, said infection can cause pulmonary inflammation and/or uncontrolled production of cytokines. In a third inventive aspect, the invention relates to the use of a compound of the present invention for the treatment of a patient diagnosed with an infection caused by a pathogen in the respiratory system, and that in certain cases can cause pulmonary inflammation and/or uncontrolled production of cytokines, through the diagnostic method of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the use of unsaturated analogs of docosanoic acid that are fundamentally characterized by having 5 or 6 double bonds in the characteristic carbon chain of this fatty acid of 22 carbon atoms, and the presence of a hydroxyl group in the C-position. 14 of the aforementioned chain, for the treatment of infections caused by a pathogen in the respiratory system. The compounds belonging to this family, in addition to the hydroxyl in position C-14, may have one or two additional hydroxyl groups, up to a total of three, also located in the carbon chain, specifically, in positions C-4, C- 7, and/or C-13.

In a first embodiment, the invention relates to an unsaturated analogue of docosanoic acid of formula (I), for the use mentioned above:

where each of Pi and P2, individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)0R ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^c R ^c , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2 to 6 membered heteroalkyl, 3 to 6 membered cycloheteroalkyl 8-membered, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4- to 11-membered cycloheteroalkylalkyl, 5- to 10-membered heteroaryl, or 6- to 16-membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c , — C(0)R ^d , — C(0)OR ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C(NOH)R ^a , — C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0 )NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n OR ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c or — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system.

In certain embodiments, Pi and P ₂ are both hydrogen atoms.

In another embodiment, the double bonds at positions 4, 10, 16, and 19 are each in the cis (Z) configuration or the double bonds at positions 4, 16, and 19 are each in the cis (Z) configuration. Z.

In another embodiment, the double bonds at positions 8 and 10 are in the trans (E) configuration.

In yet another preferred embodiment, Z is —C(0)OR ^d where R ^d for Z is other than hydrogen.

In a preferred embodiment, the C-14 hydroxyl has an S configuration.

In another preferred embodiment, the C-7 hydroxyl has an R configuration.

In another embodiment, when the pathogen is not Covid-19, the following are expressly excluded: 7R, 14S-Dihydroxy-4Z, 8E, 10E, 12Z, 16Z, 19Z-docosahexaenoic acid; 7S,14S-Dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid; Y 7S, 14S-Dihydroxy-4Z,8E, 10E, 12Z, 16Z, 19Z-docosahexaenoic acid.

In a particular embodiment, the compound of formula (I) for the aforementioned use when the pathogen is Covid-19 is the compound of formula (la):

Í¾>

In a particular embodiment, the compound of formula (I) for the aforementioned use when the pathogen is Covid-19 is the compound of formula (Ib):

Compounds (la) and (Ib) should be understood to include all pharmaceutically acceptable salts, tautomers and solvates.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (le) for the use mentioned above:

Cie) where

previously terminated. Ri is selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 heteroalkyl membered, 3 to 8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4 to 11 membered cycloheteroalkylalkyl, 5 to 10 membered heteroaryl, or 6 to 16 membered heteroarylalkyl. In a particular embodiment, Ri is a methyl or ethyl group.

In another embodiment, Pi and P ₂ are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d for Z is a hydrogen atom. In another embodiment, the double bonds at positions 4, 10, 16, and 19 are each in the cis (Z) configuration or the double bonds at positions 4, 16, and 19 are each in the cis (Z) configuration. Z. In another embodiment, the double bonds at positions 8 and 10 are in the trans (E) configuration. In another particular embodiment, the C-7 hydroxyl has an R configuration. In another particular embodiment, the C-14 hydroxyl has an S configuration.

In another particular embodiment, the invention relates to an unsaturated analogue of docosanoic acid of formula (Id) for the use mentioned above:

where

previously terminated. R1 is selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 heteroalkyl membered, 3 to 8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4 to 11 membered cycloheteroalkylalkyl, 5 to 10 membered heteroaryl, or 6 to 16 membered heteroarylalkyl. In a particular embodiment, R1 is a methyl or ethyl group.

In another embodiment, P1 and _P2 are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d for Z is a hydrogen atom. In another embodiment, the double bonds at positions 4, 10, 16, and 19 are each in the cis (Z) configuration or the double bonds at positions 4, 16, and 19 are each in the cis (Z) configuration. Z. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another particular embodiment, the C-7 hydroxyl has an R configuration. In another particular embodiment, the C-14 hydroxyl has S configuration.

(you)

where P1, _P2, =, Z, R ^a, R ^b, R ^c, R ^d, R 1, R ₂ and n are as defined above. In a particular embodiment, R1 and _R2 are independently a methyl or ethyl group.

In another embodiment, P1 and _P2 are both hydrogen atoms. In another embodiment, Z is —C(0)OR ^d where this R ^d for Z is a hydrogen atom. In another embodiment, the double bonds at positions 4, 10, 16, and 19 are each in the cis (Z) configuration or the double bonds at positions 4, 16 and 19 are each in the Z configuration. In another embodiment the double bonds at positions 8 and 10 are in the E configuration. In another particular embodiment , the C-7 hydroxyl has an R configuration. In another particular embodiment, the C-14 hydroxyl has an S configuration.

In a particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (II) for the use mentioned above:

where each of Pi and P ₂ , individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^C R ^C , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c , — C(0)R ^d , — C(0)OR ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C(NOH)R ^a , — C(NOH)NR ^c R ^c , — 0C(0)R ^d , — 0C(0)0R ^d , — 0C(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof;

In another embodiment, Pi and P ₂ are both hydrogen atoms. In another embodiment, the double bonds at positions 7, 10, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 5 and 12 are each in the Z configuration. E configuration.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (lia) for the use mentioned above:

(t¾0 where Pi, P ₂ , =

as previously defined. In a particular embodiment, Ri is a methyl or ethyl group;

In another embodiment, Pi and P ₂ are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 7, 10, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 5 and 12 are each in the Z configuration. E configuration. In another particular embodiment, the C-14 hydroxyl has an S configuration.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (I Ib) for the use mentioned above:

(;¾}

where Pi, P ₂ , = , Z, R ^a , R ^b , R ^c , R ^d , R ₂ and n are as defined above. In a particular embodiment, R ₂ is a methyl or ethyl group.

In another embodiment, Pi and P ₂ are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the doubles bonds in positions 7, 10, 16 and 19 are each in the Z configuration. In another particular embodiment, the double bonds in positions 5 and 12 are each in the E configuration. In another embodiment In particular, the C-14 hydroxyl has an S configuration.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (lie) for the aforementioned use: i!:.-·.

where Ri, P2, = , Z, R ^a , R ^b , R ^c , R ^d , R1, R2 and n are as defined above. In a particular embodiment, R1 and R2 are independently a methyl or ethyl group.

In another embodiment, P1 and _P2 are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 7, 10, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 5 and 12 are each in the Z configuration. E configuration. In another particular embodiment, the C-14 hydroxyl has an S configuration.

In a particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (III) for the use mentioned above:

where each of P1 and P2, individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)0R ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4 to 11 membered cycloheteroalkylalkyl, 5 to 10 membered heteroaryl, or 6 to 16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ 0R ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — 0S(0)R ^d , — 0S(0) ₂ R ^d , — 0S(0) ₂ 0R ^d , — 0S(0) ₂ NR ^c R ^c , — C(0)R ^d , — C(0)0R ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C(NOH)R ^a , — C(NOH)NR ^c R ^c , — 0C(0)R ^d , — 0C(0)0R ^d , — 0C(0 )NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c or — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof;

In certain embodiments, Pi and P ₂ are both hydrogen atoms.

In yet another preferred embodiment, Z is —C(0)0R ^d where R ^d for Z is hydrogen.

In a preferred embodiment, the C-14 hydroxyl has an S configuration. In another preferred embodiment, the C-7 hydroxyl has an R configuration.

In another embodiment, the double bonds at positions 4, 7, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 9 and 11 are each in the Z configuration. E configuration.

In another embodiment, when the pathogen is not Covid-19, 13R, 14S-Dihydroxy-4Z,7Z,9E, 11E, 16Z, 19Z-docosahexaenoic acid is expressly excluded.

In another particular embodiment, the invention relates to an unsaturated analog of docosanoic acid of formula (Illa) for the use mentioned above:

(girl)

where Ri, P2, = , Z, R ^a , R ^b , R ^c , R ^d , R 1 and n are as defined above. In a particular embodiment, R1 is a methyl or ethyl group.

In another embodiment, P1 and P2 are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 4, 7, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 9 and 11 are each in the Z configuration. E configuration.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (II Ib) for the use mentioned above:

(llb)

where P1, P2, = , Z, R ^a , R ^b , R ^c , R ^d , R2 and n are as defined above. In a particular embodiment, R2 is a methyl or ethyl group.

In another particular embodiment, the invention relates to an unsaturated analogue of docosanoic acid with the formula (lile) for the use mentioned above:

(little)

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (I lid) for the use mentioned above: SSd

where Ri, P2, = , Z, R ^a , R ^b , R ^c , R ^d , and n are as defined above. In another embodiment, P1 and P2 are both hydrogen atoms. In another embodiment, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 9 and 11 are each in the E configuration. .

In a particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (IV) for the aforementioned use: 8V;

where P1 is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)0R ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^C R ^C , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ 0R ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — 0S(0)R ^d , — 0S(0) ₂ R ^d , — 0S(0) ₂ 0R ^d , — 0S(0 ) ₂ NR ^c R ^c ,

— C(0)R ^d , — C(0)0R ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C( NOH)R ^a ,

— C(NOH)NR ^c R ^c , — 0C(0)R ^d , — 0C(0)0R ^d , — 0C(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , —

OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C (0)] _n R ^d , —

[NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c or — [NR ^a C(NR ^a ) ] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system.

In another embodiment, Pi is a hydrogen atom. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 4, 7, 10, 16, and 19 are each in the Z configuration. In yet another particular embodiment, the double bond at position 12 is in the E configuration.

In another particular embodiment, when the pathogen is not Covid-19, the following are expressly excluded: 14-H hydroxy-4Z, 7Z, 10Z, 12Z, 16Z, 19Z-docosahexaenoic acid; 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid; Y

Ethyl 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoate.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (IVa) for the use mentioned above: ii.V

where Pi, = , Z, R ^a , R ^b , R ^c , R ^d , Ri, and n are as defined above. In another embodiment, Pi is a hydrogen atom. In another embodiment Ri is methyl or ethyl. In another embodiment, Z is —C(0)OR ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 4, 7, 10, 16, and 19 are each of them in the Z configuration. In another particular embodiment, the double bond in position 12 is in the E configuration.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (IVb) for the use mentioned above:

SVh;

where P1, = , Z, R ^a , R ^b , R ^c , R ^d , and n are as defined above. In another embodiment, P1 is a hydrogen atom. In another embodiment, Z is —C(0)0R ^d where this R ^d for Z is other than hydrogen. In another embodiment, the double bonds at positions 7, 10, 16, and 19 are each in the Z configuration. In yet another particular embodiment, the double bond at position 12 is in the E configuration.

In a particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (V) for the use mentioned above:

(V)

where each of P1, P2 and P3 individually is a protecting group or a hydrogen atom and — Z, R ^a , R ^b , R ^c , R ^d and n are as defined above.

In one aspect, P1, P2, and Ps are all hydrogen atoms.

In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. .

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (Va) for the use mentioned above:

where Ri, P2 and P3 _, Z, R ^a , R ^b , R ^c , R ^d , R 1 and n are as defined above. In one aspect, P1, P2, and P3 are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another particular aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, Ri is a methyl or an ethyl group.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (Vb) for the use mentioned above:

(Vb) where

as previously defined.

In one aspect, P1, P2, and Ps are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, R ₂ is a methyl or an ethyl group.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (Ve) for the use mentioned above:

(Go) where

as previously defined. In one aspect, P1, _P2 and P3 are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, R3 is a methyl or an ethyl group.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (Vd) for the use mentioned above:

(You)

where Ri, P ₂ and P ₃ , Z, R ^a , R ^b , R ^c , R ^d , R ₁ , R ₂ and n are as defined above. In one aspect, Ri, P ₂ and P ₃ are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, R and R are independently a methyl or ethyl group.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (Ve) for the use mentioned above: íVei where

as previously defined. In one aspect, P ₁ , P ₂ and P ₃ are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, R ₁ and R ₃ are independently a methyl or ethyl group.

In another particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (Vf) for the use mentioned above:

(Saw)

where P ₁ , P ₂ and P ₃ , Z, R ^a , R ^b , R ^c , R ^d , R ₂ , R ₃ and n are as defined above. In one aspect, P ₁ , P ₂ and P ₃ are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another aspect, the double bonds at positions 5, 9, and 11 are each in the E configuration. In another aspect, R ₂ and R ₃ are independently a methyl or ethyl group.

In another particular embodiment, the invention refers to an unsaturated analog of docosanoic acid of formula (Vg) for the use mentioned above: where Pi, P ₂ and P ₃ , =, Z, R ^a , R ^b , R ^c , R ^d , R ₁ , R ₂ , R ₃ and n are as defined above. In one aspect, Pi, P ₂ and P ₃ are all hydrogen atoms. In another aspect, the double bonds at positions 7, 16, and 19 are each in the Z configuration. In another particular embodiment, the double bonds at positions 5, 9, and 11 are each in the Z configuration. E. In another aspect, R ₁ , R ₂ and R ₃ are independently a methyl or ethyl group.

In a particular embodiment, the invention refers to an unsaturated analogue of docosanoic acid of formula (VI) for the use mentioned above:

where P1, _P2, =, Z, R ^a, R ^b, R ^c, R ^d, and n are as defined above. In another embodiment, P1 and _P2 are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d para is a hydrogen atom. In another embodiment, the double bonds at positions 4, 12, 16, and 19 are each in the Z configuration. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another embodiment , the 7-position hydroxyl is in the R configuration. In another embodiment, the 14-position hydroxyl is in the S configuration.

In another embodiment, the invention relates to an unsaturated analogue of docosanoic acid of formula (Via) for the use mentioned above:

where P1, _P2, =, Z, R ^a, R ^b, R ^c, R ^d, R1, and n are as defined above. In another embodiment, P1 and _P2 are both hydrogen atoms. In other embodiment, Z is — C(0)0R ^d where this R ^d for Z is a hydrogen atom. In another embodiment Ri is a methyl or ethyl group. In another embodiment, the double bonds at positions 4, 12, 16, and 19 are each in the Z configuration. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another embodiment , the 7-position hydroxyl is in the R configuration. In another embodiment, the 14-position hydroxyl is in the S configuration.

In another embodiment, the invention relates to an unsaturated analogue of docosanoic acid of formula (VI b) for the use mentioned above:

where Ri, P2, = , Z, R ^a , R ^b , R ^c , R ^d , R2, and n are as defined above. In another embodiment, P1 and P2 are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d for Z is a hydrogen atom. In another embodiment R ₂ is a methyl or ethyl group. In another embodiment, the double bonds at positions 4, 12, 16, and 19 are each in the Z configuration. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another embodiment , the 7-position hydroxyl is in the R configuration. In another embodiment, the 14-position hydroxyl is in the S configuration.

In another embodiment, the present invention relates to an unsaturated analogue of docosanoic acid of formula (Vlc) for the use mentioned above:

where P1, _P2, =, Z, R ^a, R ^b, R ^c, R ^d, R 1, R ₂ and n are as defined above. In another embodiment, P1 and _P2 are both hydrogen atoms. In another embodiment, Z is —C(0)OR ^d where this R ^d for Z is a hydrogen atom. In another embodiment R1 and R2, independently, are a methyl or ethyl group. In another embodiment, the double bonds at positions 4, 12, 16, and 19 are each one of them in the Z configuration. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another embodiment, the hydroxyl at position 7 is in the R configuration. In another embodiment, the hydroxyl at position 14 is in the S configuration.

In another embodiment, the present invention relates to an unsaturated analogue of docosanoic acid of formula (Vid) for the use mentioned above:

(Vine)

where Ri, P, =, Z, R ^a , R ^b , R ^c , R ^d , and n are as defined above. In another embodiment, P and P are both hydrogen atoms. In another embodiment, Z is —C(0)0R ^d where this R ^d is a hydrogen atom. In another embodiment, the double bonds at positions 12, 16, and 19 are each in the Z configuration. In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another embodiment, the The 7-position hydroxyl is in the R configuration. In another embodiment, the 14-position hydroxyl is in the S configuration.

In a particular embodiment, the invention relates to an unsaturated analogue of docosanoic acid of formula (VII) for the use mentioned above:

where Ri, R, = , Z, R ^a , R ^b , R ^c , R ^d , and n are as defined above.

In another embodiment, P and P are both hydrogen atoms. In another embodiment, the double bonds at positions 12, 16, and 19 are each in the cis (Z) configuration or the double bonds at positions 16 and 19 are each in the cis (Z) configuration. . In another embodiment, the double bonds at positions 8 and 10 are in the E configuration. In another particular embodiment, the C-7 hydroxyl has an R configuration. In another particular embodiment, the C-14 hydroxyl has an S configuration. In another particular embodiment, when the pathogen is not Covid-19, 7,14-Dihydroxy-8E,10E,12Z,16Z,19Z-eicosapentaenoic acid is expressly excluded.

In another particular embodiment, the present invention provides the use of pharmaceutical compositions comprising one or more compounds of the invention, with or without other active pharmaceutical ingredients, in admixture with a pharmaceutically acceptable vehicle, for the treatment of an infection caused by a pathogen. in the respiratory system. Such a composition can be administered in accordance with the methods of the present invention.

In another embodiment, the present invention is based on the use of a compound of the invention, or a composition (for example, a nutritional supplement or a food-drug) or a pharmaceutical composition comprising a compound of the present invention, where expressly excludes the compounds of formula (IV) 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid, and ethyl 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoate, for the treatment or prevention of a cytokine release syndrome or cytokine storm syndrome infection in a mammal. The use or treatment involves the administration of a prophylactically or therapeutically effective amount of at least one compound of the invention, a composition, or a pharmaceutical composition thereof.

In another more preferred embodiment, the compound of the invention, composition (for example, a nutritional supplement or a food-drug) or pharmaceutical composition comprising at least one compound of the present invention can be used to treat or prevent an infection selected from viral pneumonia, bacterial pneumonia, or atypical pneumonia.

In another embodiment, the compound of the invention, composition (for example, a nutritional supplement or a food-drug) or pharmaceutical composition comprising at least one compound of the present invention can be used to treat or prevent an infection caused by a pathogen in the respiratory system and that present with pulmonary inflammation.

In another more preferred embodiment, the compound of the invention, composition (for example, a nutritional supplement or a food-drug) or pharmaceutical composition comprising at least one compound of the present invention can be used to treat or prevent an infection selected from pneumonia, bacterial pneumonia, viral pneumonia, atypical pneumonia, graft disease against host (GVHD), coronavirus disease 2019 (COVID-19), reduction of the viral load of Covid-19, SARS-CoV1, Ebola, avian influenza, smallpox, or common influenza, by administration to an individual who need, of an effective amount of any one of the compounds, compositions or pharmaceutical compositions described herein.

In another embodiment, the compounds of the invention, compositions (eg, a nutritional supplement or a food-drug), or pharmaceutical compositions comprising at least one compound of the present invention can be used to treat or prevent a viral infection.

In another more preferred embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-drug) or pharmaceutical compositions comprising at least one compound of the present invention can be used to treat or prevent viral pneumonia.

In another even more preferred embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-drug) or pharmaceutical compositions comprising at least one compound of the present invention can be used to treat or prevent a disease selected from between COVID-19, SARS-CoV1, sepsis, Ebola, avian flu, smallpox, or common flu.

In another even more preferred embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-medicine) or pharmaceutical compositions that comprise at least one compound of the present invention can be used to treat or prevent COVID-19 .

In another embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-drug) or pharmaceutical compositions that comprise at least one compound of the present invention can be used to treat or prevent an infection that causes the syndrome of acute respiratory distress (ARDS), severe acute respiratory syndrome (SARS), systemic inflammatory response syndrome (SIRS), thrombocytopenia syndrome (TFSS), or pancreatitis.

In another more preferred embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-drug) or pharmaceutical compositions that comprise at least one compound of the present invention can be used to treat or prevent an infection that occurs with acute respiratory distress syndrome (ARDS), or severe acute respiratory syndrome (SARS). In another embodiment, the compounds of the invention, compositions (for example, a nutritional supplement or a food-drug) or pharmaceutical compositions that comprise at least one compound of the present invention can be used to treat or prevent an infection that causes pancreatitis.

Serhan CN et al., US10568858 describes compositions comprising at least one compound of the present invention, such as, for example, the compound of formula (IV) 14-HDHA or 14-hydroxy acid-4Z,7Z,10Z,12E, 16Z,19Z-docosahexaenoic, and other compounds such as 17-HDHA, 18-HEPE, 4-HDHA and 10-HDHA both in its free form as ethyl ester, triglyceride, diglyceride, monoglyceride or mixtures thereof, for the treatment of diseases that cause inflammation. In this patent, the synergistic effect of a mixture of several long-chain polyunsaturated and hydroxylated fatty acids is shown. Compositions such as those described in US10568858 are marketed under the name of Lipinova ^® .

In another embodiment, the present invention relates to the use, as mentioned above, of any one of the pharmaceutical compositions, comprising one or more compounds of the present invention, as defined by formulas (I), (the ), (Ib), (le), (Id), (le), (II), (lia), (llb), (lie), (III), (Illa), (lllb), (lile), (II Id), (IV), (IVa), (IVb), (V), (Va), (Vb), (Ve), (Vd), (Ve), (Vf), (Vg), ( VI), (Via), (Vlb), (Vio), (Vid), and (Vil), and the compounds: 17-HDHA (17-hydroxy- 4Z,7Z, 10Z, 13Z, 15E, 19Z-docosahexaenoic acid ) and 18-HEPE (18-hydroxy-5Z, 8Z, 11 Z, 14Z, 16E-eicosa-pentaenoic acid).

In another more preferred embodiment, the present invention relates to the use, as mentioned above, of a pharmaceutical composition comprising at least one compound of formula (IV), and the compounds 17-HDHA and 18-HEPE.

In another more preferred embodiment, the present invention relates to the use, as mentioned above, of a pharmaceutical composition comprising 14-HDHA, 17-HDHA and 18-HEPE.

In another more preferred embodiment, the present invention relates to the use, as mentioned above, of a nutritional supplement, or a food-drug (medical food in English) comprising at least one of the compounds of the invention defined according to the formulas (I), (la), (Ib), (le), (Id), (le), (If), (II), (lia), (llb), (lie), (III), (Illa), (lllb), (lile), (llld), (IV), (IVa), (IVb), (V), (Va), (Vb), (Ve ), (Vd), (Ve), (Vf), (Vg), (VI), (Via), (Vlb), (Vlc), or (Vid), and the compounds 17-HDHA and 18-HEPE.

In a more preferred embodiment, the present invention relates to the use, as mentioned above, of a nutritional supplement or food-medication comprising at least one compound of formula (IV), and the compounds 17-HDHA and 18 -HEPE.

In an even more preferred embodiment, the present invention relates to the use, as mentioned above, of a nutritional supplement comprising 14-HDHA, 17-HDHA and 18-HEPE.

In another even more preferred embodiment, 14-HDHA is present in the pharmaceutical composition, nutritional composition, food-drug, or nutritional supplement, in an amount of 0.0002% by weight to 10% by weight, for example, 0.0002 ,

0.0004, 0.0006, 0.0008, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2% by weight, 0.22% by weight, 0.24 wt%, 0.26 wt%, 0.28 wt%, 0.3 wt%, 0.32 wt%, 0.34 wt%, 0.36 wt%, 0 0.38 wt%, 0.4 wt%, 0.42 wt%, 0.44 wt%, 0.46 wt%, 0.48 wt%, 0.5 wt%, 0, 52 wt%, 0.54 wt%, 0.56 wt%, 0.58 wt%, 0.6 wt%, 0.62 wt%, 0.64 wt%, 0.66 % by weight, 0.68% by weight, 0.7% by weight, 0.72% by weight, 0.74% by weight, 0.76% by weight, 0.78% by weight, 0.8% by weight, 0.82% by weight, 0.84% by weight, 0.86% by weight, 0.88% by weight, 0.9% by weight, 0.92% by weight, 0.94% by weight wt, 0.96 wt%, 0.98 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt% , 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7, 0% by weight, 7 0.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, or 10.0 wt%.

In a preferred embodiment, 14-HDHA is present in an amount between 0.008% by weight and 10.0% by weight.

In another even more preferred embodiment, 17-HDHA is present in the pharmaceutical composition, nutritional composition, food-medication, or supplement nutritional, in an amount from 0.0002% by weight to 10% by weight, for example, 0.0002, 0.0004, 0.0006, 0.0008, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007 , 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.12, 0 0.14, 0.16, 0.18, 0.2 wt%, 0.22 wt%, 0.24 wt%, 0.26 wt%, 0.28 wt%, 0.3% by weight, 0.32% by weight, 0.34% by weight, 0.36% by weight, 0.38% by weight, 0.4% by weight, 0.42% by weight, 0.44% by weight wt, 0.46 wt%, 0.48 wt%, 0.5 wt%, 0.52 wt%, 0.54 wt%, 0.56 wt%, 0.58 wt% , 0.6 wt%, 0.62 wt%, 0.64 wt%, 0.66 wt%, 0.68 wt%, 0.7 wt%, 0.72 wt%, 0.74 wt%, 0.76 wt%, 0.78 wt%, 0.8 wt%, 0.82 wt%, 0.84 wt%, 0.86 wt%, 0 .88 wt%, 0.9 wt%, 0.92 wt%, 0.94 wt%, 0.96 wt%, 0.98 wt%, 1.0 wt%, 1, 5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% and n wt, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt% wt, 8.5 wt%, 9.0 wt%, 9.5 wt%, or 10.0 wt%.

In another preferred embodiment, 17-HDHA is present in an amount between 0.009% by weight and 10.0% by weight.

In another even more preferred embodiment, 18-HEPE is present in the pharmaceutical composition, nutritional composition, food-drug, or nutritional supplement, in an amount of 0.0002% by weight to 10% by weight, for example, 0.0002 ,

0.0004, 0.0006, 0.0008, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2% by weight, 0.22% by weight, 0.24 wt%, 0.26 wt%, 0.28 wt%, 0.3 wt%, 0.32 wt%, 0.34 wt%, 0.36 wt%, 0 0.38 wt%, 0.4 wt%, 0.42 wt%, 0.44 wt%, 0.46 wt%, 0.48 wt%, 0.5 wt%, 0, 52 wt%, 0.54 wt%, 0.56 wt%, 0.58 wt%, 0.6 wt%, 0.62 wt%, 0.64 wt%, 0.66 % by weight, 0.68% by weight, 0.7% by weight, 0.72% by weight, 0.74% by weight, 0.76% by weight, 0.78% by weight, 0.8% by weight, 0.82% by weight, 0.84% by weight, 0.86% by weight, 0.88% by weight, 0.9% by weight, 0.92% by weight, 0.94% by weight wt, 0.96 wt%, 0.98 wt%, 1 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 % by weight, 4.0% by weight, 4.5% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, 7.0% by weight, 7.5% by weight, 8.0% by weight, 8.5% by weight, 9.0% by weight, 9.5% by weight, or 10.0% in weigh.

In another preferred embodiment, 18-HEPE is present in an amount between 0.02% by weight and 10.0% by weight.

In another more preferred embodiment, 17-HDHA is present in an amount between 0.009% by weight and 10.0% by weight, 18-HEPE is present in an amount between 0.01% by weight and 10.0% by weight, and 14-HDHA is present in an amount between 0.008% by weight and 10.0% by weight.

In another more preferred embodiment, 17-HDHA is present in an amount between 0.01% by weight and 10.0% by weight, 18-HEPE is present in an amount between 0.01% by weight and 10.0% by weight. weight, and 14-HDHA is present in an amount between 0.008 wt% and 10.0 wt%.

It is understood in the present invention that the compounds of the present invention, especially the 14-HDHA compound, and the 17-HDHA and 18-HEPE compounds can be found in a pharmaceutical composition, in a nutritional supplement or in a food-medication in the free form (free acid), as esters, ethyl esters, triglycerides, diglycerides, monoglycerides, sphingolipids, phospholipids, or as mixtures thereof.

The nutritional supplements or medical foods of the present invention may include one or more active ingredients, such as aspirin, curcumin, polyphenols, lutein, astaxanthin, and/or one or more vitamins selected from vitamin D, vitamin A, vitamin E and/or or vitamin K.

A second inventive aspect, the present invention comprises a method for diagnosing and/or monitoring the condition of a patient suffering from a disease caused by the presence of a pathogen in the respiratory system based on the identification of pro-resolving lipid mediators and the quantification of their concentration, in the blood, plasma, and/or serum of said patient, which are relevant in said disease.

In the human body, more than 70 lipid mediators related to inflammation have been identified that show a pro-inflammatory action (such as, prostaglandins, thromboxanes, and leukotrienes) and/or pro-resolution (in W0201317006 you can find an extensive list of this type of mediators).

The concentration of lipid mediators, both pro-inflammatory and pro-resolution, varies in a subject depending on whether they suffer from a pathology, disease, infection, insult, or aggression compared to a subject considered healthy, that is, a subject who lacks a pathology, disease, infection, insult, or any aggression. In a preferred embodiment, the diagnostic method of the present invention refers to the identification of a set of five lipid mediators with pro-resolution action formed by: RvE1 (acid 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z ,16E- eicosapentaenoic), RvD2 (7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z- docosahexaenoic acid), RvD4 (4S,5,17S-trihydroxy-6E,8E,10E,13E ,15Z,19Z- docosahexaenoic), MaR1 (7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid), and PDX (10S,17S-dihydroxy-4Z,7Z,11E,13Z, 15E,19Z-docosahexaenoic), whose variations are relevant.

Surprisingly, by identifying and measuring the concentration of a large number of lipid mediators, through blood analysis of a series of individuals, it has been found that the variations in concentration of the aforementioned four lipid mediators in blood, plasma and/or or serum, are related to the condition of a subject in relation to one of the diseases described in the present invention. In this way, it can be determined whether a subject is healthy or suffers from a disease caused by a pathogen in the respiratory system by analyzing the aforementioned pro-resolving lipid mediators in blood, plasma, and/or serum. In addition, obtaining and analyzing the values in blood, plasma, and/or serum of the aforementioned lipid mediators allow monitoring the evolution of a patient suffering from a disease such as those described in the present invention.

Examples of procedures for obtaining concentration values of lipid mediators of the present invention in blood, plasma, and/or serum can be found in WO2018098244, Serhan C. N., et al and/or WO2019057756A1, Dalli J., et al.

In a preferred embodiment, the set of pro-resolving lipid mediators is composed of RvE1, RvD2, MaR1 and PDX.

In a preferred embodiment, the set of pro-resolving lipid mediators is composed of RvD2, MaR1 and PDX.

In a more preferred embodiment, the set of pro-resolving lipid mediators is composed of MaR1 and PDX. In a more preferred embodiment, the diagnosis and/or follow-up method of a patient suffering from a disease as mentioned above is carried out by means of the identification and quantification of MaR1.

In a preferred embodiment, the concentration values of the pro-resolving lipid mediators are measured in plasma.

In another preferred embodiment, the concentration values of the pro-resolving lipid mediators are measured in serum.

In another preferred embodiment, the measurement of the concentration values of the pro-resolving lipid mediators is carried out in tissue and/or fluids of the respiratory system.

In another more preferred embodiment, the concentration values of the pro-resolving lipid mediators are measured in plasma and serum.

In another preferred embodiment, the concentration values of the pro-resolving lipid mediators are measured in serum, where the blood sample is treated with an adenosine inhibitor, such as adenosine deaminase (ADA), caffeine (1 ,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione), 8- (3-chlorostyryl)caffeine, 2-phenylaminoadenosine, 2-p-2 -carboxyethylphenylamino-5'-N- ethylcarboxamido-adenosine, 5-N-ethylcarboxamido-adenosine, 5'-N-cyclopropyladenosine, 5'N-methylcarboxamidoadenosine, PD-1259444, 1,3-dipropyl-phenylxanthine, or 4-{2 -[7- amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a]-[1,3,5]-triazin-5-ylamino]ethyl}phenol, also known as ZM 241385.

In a more preferred embodiment, in addition to the identification and measurement of the concentration values of the pro-resolving lipid mediators RvE1, RvD2, RvD4, MaR1 and PDX, a set of so-called pro-inflammatory lipid mediators formed by: PGD2 (Prostaglandin D2, or 9a,15S-dihydroxy-11-oxo-prosta-5Z,13E-dien-1-oic acid) and LTB4 (Leukotriene B4 or 5S,12R-dihydroxy-6Z,8E,10E acid, 14Z-eicosatetraenoic), whose identification and quantification of its concentration in blood, plasma, and/or serum allows obtaining additional information that complements or improves the diagnosis and/or follow-up of a subject suffering from one of the diseases described in this invention.

In an even more preferred embodiment, the identification and measurement of the concentration values of the pro-resolving lipid mediators RvD2, MaR1 and PDX, and the pro-inflammatory mediator LTB4 is carried out.

In a preferred embodiment, the measurement of the concentration values of the pro-inflammatory mediators is carried out in plasma. In another preferred embodiment, the concentration values of the pro-inflammatory mediators are measured in serum.

In another more preferred embodiment, the concentration values of the pro-inflammatory lipid mediators are measured in plasma and serum.

In another preferred embodiment, the concentration values of pro-inflammatory lipid mediators are measured in serum, where the blood sample is treated with an adenosine inhibitor, such as adenosine deaminase (ADA), caffeine (1 ,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione), 8- (3-chlorostyryl)caffeine, 2-phenylaminoadenosine, 2-p-2 -carboxyethylphenylamino-5'-N- ethylcarboxamido-adenosine, 5-N-ethylcarboxamido-adenosine, 5'-N-cyclopropyladenosine, 5'N-methylcarboxamidoadenosine, PD-1259444, 1,3-dipropyl-phenylxanthine, or 4-{2 -[7- amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a]-[1,3,5]-triazin-5-ylamino]ethyl}phenol, the latter it is also known as ZM 241385.

In another preferred embodiment, the measurement of the concentration values of the pro-inflammatory lipid mediators is performed in serum, where the blood sample is treated with ADA.

In another preferred embodiment, the measurement of the concentration values of the pro-inflammatory lipid mediators is performed in serum, where the blood sample is treated with caffeine.

The authors of the present invention have found that severe or very severe patients with diseases caused by the presence of a pathogen in the respiratory system and that, in certain cases, may present with an uncontrolled production of cytokines, have altered levels of lipid mediators. compared to healthy subjects. Thus, the so-called pro-resolution lipid mediators are found at levels lower than the values established for healthy individuals, while the so-called pro-inflammatory lipid mediators are found at levels higher than those found in healthy individuals.

In a preferred embodiment, the diagnosis and/or follow-up method allows a positive result, that is, that a subject suffers from any of the pathologies described in the present invention when a decrease of at least 30% is observed, with respect to a healthy individual, of the concentration in blood, plasma and/or serum of each of the components of the set of pro-resolution lipid mediators. In a more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 40%, with respect to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 50%, with respect to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 60%, with respect to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 70%, with respect to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 80%, with respect to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 90%, with respect to a healthy individual.

In a preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 30%, 35%, 40%, 45%, 50%, 55%, a 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, while the increase in PGD2 is at least 200%, 250%, 300%, 350%, 400%, 450%, and LTB4 increase is at least 100%, 150%, 200%, 250%, relative to an individual healthy. In a more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 40%, and an increase of at least 200% in each of the pro-inflammatory mediators, PGD2 and LTB4, relative to a healthy individual.

In a more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least 40%, and an increase in pro-inflammatory mediators is at least 300% PGD2, and of at least 200% of LTB4, compared to a healthy individual.

In an even more preferred embodiment, the decrease in each of the components of the set of pro-resolution lipid mediators is at least one 40%, and an increase in proinflammatory mediators of at least 400% of PGD2, and of at least 200% of LTB4, compared to a healthy individual.

In an even more preferred embodiment, the increase in the pro-inflammatory mediator LTB4 is at least 100%, compared to a healthy individual.

In a preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system is a disease that also causes cytokine release syndrome or cytokine storm syndrome in a mammal.

In another more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system where the disease is selected from: pneumonia, bacterial pneumonia, viral pneumonia, atypical pneumonia, graft disease against host (GVHD), coronavirus disease 2019 (COVID-19), SARS-CoV1, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, Ebola, avian influenza, smallpox, inflammatory response syndrome (SIRS), thrombocytopenia syndrome (SFTS), common flu, and pancreatitis.

In another more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system where the disease is selected from: viral pneumonia, bacterial pneumonia, and atypical pneumonia.

In another even more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system is viral pneumonia.

In another more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system is selected from: COVID-19, SARS-CoV1, sepsis, Ebola, avian influenza, smallpox, and common flu.

In another even more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system is Covid-19.

In another embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system is selected from: acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), systemic inflammatory response (SIRS), thrombocytopenia syndrome (SFTS), and pancreatitis. In another more preferred embodiment, the method of diagnosis and/or monitoring of a disease caused by the presence of a pathogen in the respiratory system selected from: acute respiratory distress syndrome (ARDS), and severe acute respiratory syndrome (SARS) .

In another embodiment, the disease related to the diagnostic and/or monitoring method of the present invention is pancreatitis.

In another embodiment, the disease related to the diagnostic and/or monitoring method of the present invention is a viral infection.

In a third inventive aspect, the invention refers to the use of a compound, a composition (such as, for example, a nutritional supplement or a food-medicine), or a pharmaceutical composition, of the present invention for the treatment of a patient diagnosed with through the diagnostic method of the present invention.

Additional features and advantages of the invention will become more apparent from the following detailed description and claims.

While multiple embodiments are described, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description. As will be apparent, the invention is capable of modifications in several obvious respects, all without departing from the spirit and scope of the present invention. Accordingly, the detailed descriptions are to be considered illustrative and not restrictive in nature.

In the specification and claims, the terms "includes" and "comprises" are open-ended terms and should be interpreted to mean "includes but is not limited to." These terms encompass the more restrictive terms “consists essentially of” and “consists of”.

It should be noted that, as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Also the terms "a" (or "an"), "one or more" and "at least one" may be used interchangeably herein. It is also to be noted that the terms "comprise", "includes" characterized by" and "has" may be used interchangeably.

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as are commonly understood by one skilled in the art to which this invention pertains. All references cited in this specification are to be taken as indicative of the level of knowledge on the subject. Nothing herein is to be construed as administering that the invention is not entitled to preempt such disclosure by virtue of the prior invention.

"Compounds of the invention" refers to the mono-, di- and trihydroxylated analogs of docosanoic acid that also have 5 or 6 double bonds in their carbon chain of 22 carbon atoms, and compounds encompassed by the generic formulas disclosed in herein, and include any specific compound of these formulas whose structure is disclosed herein. The compounds of the invention can be identified by their chemical structure and/or chemical name. When the chemical structure and the chemical name do not correspond, the chemical structure will determine the identity of the compound. The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double bond isomers (specifically geometric isomers), or enantiomers or diastereomers as they present different S and S configurations. R at each chiral center. Accordingly, the chemical structures depicted herein encompass all possible enantiomers, epimers, diastereomers, and stereoisomers of the illustrated compounds, including the stereoisomerically pure form (eg, geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric mixtures. and stereoisomeric. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomeric or stereoisomeric components using separation techniques or asymmetric synthesis techniques well known to those skilled in the art. The compounds of the invention also include isotopically labeled compounds in which one or more atoms have an atomic mass other than the atomic mass conventionally found in nature.

Compounds depicted throughout the specification contain ethylenically unsaturated sites. When carbon-carbon double bonds exist, the configurational chemistry may be cis (Z) or trans (E) and representations throughout the specification are not intended to be limiting. The representations are generally presented based on the configurational chemistry of related DHA, DPA, or EPA compounds, and while not limited in theory, are believed to possess similar configurational chemistry. The use of — reflects this throughout the specification and claims, so both are contemplated. cis and trans isomers. In certain embodiments, the configuration of the ethylenic bond is known and is particularly described.

For clarity, the use of “ — ” in parallel to a carbon-carbon bond in the Markush formulas of the present invention indicates the existence of a double bond that can have a cis (Z) configuration or a trans (E) configuration, regardless of the E or Z configuration that appears in a given double bond “=” in a given Markush formula.

"Biological activity" and its contextual equivalents "activity" and "bioactivity" mean that a compound elicits a statistically valid effect in any biological test assay. Preferably, the threshold for defining an "active" compound will be reproducible and statistically valid effects of at least 25% deviation from the untreated control at concentrations of 1 microM or less.

"Biological test assay" means a specific experimental procedure. Non-limiting examples of biological test assays include: 1) ligand binding, direct or indirect, to a purified target, subcellular fraction, intact cell, or cell or tissue extract; 2) metabolic protection with enhanced half-life when exposed to a purified target, subcellular fraction, intact cell, cell extract, or tissue, or administered to the intact organism by any route; 3) prevention, reversal, or enhancement of cell- and tissue-based functional responses recognized by those skilled in the art to represent proxies for anti-inflammatory action, such as altered cytokine production and release, and 4) prevention, reversal, or enhancement of symptoms and/or pathological processes in animal models of inflammation and inflammatory disease in relation to the release of cytokines. "Detectable label" means any chemical or biological modality that can be used to track, trace, locate, quantify, immobilize, purify, or identify compounds by appropriate detection means known in the art. Non-limiting examples of detectable labels include labeling of fluorescence, phosphorescence, luminescence, radioactive or biospecific affinity capture.

"Electronegative group" is a chemical group that tends to gain, rather than lose, electrons in its chemical interactions. Examples of electronegative groups include, but are not limited to -N02, ammonium salts, sulfonyl groups, carbonyl groups, halogens, esters, carboxylic acids, nitriles, etc. "in situ" refers to and includes the terms "in vivo", "ex vivo", and "in vitro" as these terms are commonly recognized and understood by one skilled in the art. Furthermore, the phrase "in situ" is used herein in the broader connotative and denotative context to identify an entity, cell, or tissue as found or in its place, regardless of its source or origin, its condition or state, or its duration or longevity in that location or position.

“Pharmaceutically acceptable” means approved by a federal or state government regulatory agency or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) salts formed when a basic proton is present in the parent compound such as acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or those formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton is present in the parent compound and is replaced by a metal ion, eg, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, W-methylglucamine, triethylamine, propylamino, diazabicycloundecane, and the like. "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound of the invention is administered.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or carrier such as a liquid or solid carrier, diluent, excipient, solvent, or encapsulating material involved in carrying or transporting a compound(s) of the present invention in or to the subject in such a way that it can perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol; phosphate buffer solutions and other compatible non-toxic substances used in pharmaceutical formulations. "Prodrug" refers to a derivative of a drug molecule that requires transformation in the body to release the active drug. Prodrugs are often (but not necessarily) pharmacologically inactive until converted to the parent drug. A hydroxyl-containing drug can be converted, for example, to a sulfonate, ester, or carbonate prodrug, which can be hydrolyzed in vivo to provide the hydroxyl compound. An amino-containing drug can be converted, for example, to a carbamate, amide, imine, phosphonyl, phosphoryl, or sulfenyl prodrug, which can be hydrolyzed in vivo to provide the amino compound. A carboxylic acid drug can be converted to an ester (include silyl esters and thioesters), amide, or hydrazide prodrug, which can be hydrolyzed in vivo to provide the carboxylic acid compound. Prodrugs for drugs containing different functional groups other than those listed above are well known to those skilled in the art.

"Promoiety" refers to a form of protecting group that, when used to mask a functional group on a drug molecule, converts the drug in a prodrug. Typically, the promoiety will be attached to the drug through a bond or bonds that are cleaved by enzymatic or non-enzymatic means in vivo.

"Protective group" refers to a grouping of atoms that, when bound to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Examples of protective groups can be found in Green et al., "Protective Groups in Organic Chemistry," (Wiley, 2nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods," Vol. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("SES"), trityl, and trityl groups substituted, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (e.g., methyl esters). and ethyl, acet groups to or propionate or glycol esters) or alkylated such as trityl ethers, alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (eg TMS or TIPPS groups) and allyl ethers.

"Subject" means living organisms susceptible to conditions or diseases caused or contributed to by the cytokine storm. Examples of subjects include humans, dogs, cats, cows, goats, and mice. The term "subject" is intended to further include transgenic species such as, for example, transgenic mice.

"Alkyl," by itself or as part of another substituent, refers to a monovalent, branched, linear or cyclic, saturated or unsaturated hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means from 1 to 6 carbon atoms) and which is derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-l-en-2-yl, prop-2-en-

1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methylpropan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but -1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-

2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-l-en-3- yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. and the like. When specific levels of saturation are intended, the nomenclature is used. "alkanyl", "alkenyl" and/or "alkynyl", as defined below. In preferred embodiments, the alkyl groups are (C1-C6)alkyl.

"Alkanyl", by itself or as part of another substituent, refers to a branched, linear, or saturated cyclic alkyl derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanol; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methylpropan-2-yl (tert-butyl), cyclobutan-1- ilo, etc. and the like. In preferred embodiments, the alkanyl groups are (C1-C6)alkanyl.

"Alkenyl," by itself or as part of another substituent, refers to an unsaturated, branched, linear, or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom. carbon of an original alkene. The group may be in the cis (Z) or trans (E) conformation around the double or double bonds. Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1 -ilo; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-2-en -2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta - 1,3-dien-1-yl, etc. and the like. In preferred embodiments, the alkenyl group is (C2-C6)alkenyl.

"Alkynyl," by itself or as part of another substituent, refers to an unsaturated, branched, linear, or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of a hydrogen atom from a single carbon atom. of an original alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. and the like. In preferred embodiments, the alkynyl group is (C2-C6)alkynyl.

"Alkyldiyl", by itself or as part of another substituent, refers to a saturated or unsaturated divalent branched, linear, or cyclic hydrocarbon group having the stated number of carbon atoms (specifically, C1-C6 means 1 to 6 carbon atoms). carbon) derived from the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene, or alkyne, or from the removal of two hydrogen atoms from a single carbon atom of an alkane, alkene or original alkyne The two monovalent radical centers of each valence of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methanediyl; ethyldiyls such as ethane-1,1-diyl, ethane-1,2-diyl, ethene-1,1-diyl, ethene-1,2-diyl; propyldiyls such as propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, propane-1,3-diyl, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl , prop-1-ene-1,1-diyl, prop-1-ene-1.2-diyl, prop-2-ene-1,2-diyl, prop-1-ene-1,3-diyl, cycloprop-1 -ene-1,2-diyl, cycloprop-2-ene-

1,2-diyl, cycloprop-2-ene-1,1-diyl, prop-1-yne-1,3-diyl, etc.; butyldiyls such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,2-diyl, 2-methylpropane-1,1 -diyl, 2-methylpropane-1,2-diyl, cyclobutane-1, 1-diyl; cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, but-1-ene-1,1-diyl, but-1-ene-1,2-diyl, but-1-ene-1,3-diyl, but-1-ene-1 ,4-diyl, 2- methylprop-1-ene-1, 1-diyl, 2-methanylidenepropane-1, 1-diyl, buta-

1,3-diene-1,1-diyl, buta-1,3-diene-1,2-diyl, buta-1,3-diene-1,3-diyl, buta-1,3-diene-

1,4-diyl, cyclobut-l-ene-1,2-diyl, cyclobut-1-ene-1,3-diyl, cyclobut-2-ene-1,2-diyl, cyclobuta-1,3-diene-1, 2-diyl, cyclobuta-1,3-diene-1,3-diyl, but-1-yne-1,3-diyl, but-1-yne-1,4-diyl, buta-1,3-diyno- 1,4-diyl, etc. and the like. When specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl, and/or alkynyldiyl is used. When the two valences are specifically intended to be on the same carbon atom, the nomenclature "alkylidene" is used. In preferred embodiments, the alkyldiyl group is C1-C6 alkyldiyl. Saturated acyclic alkanediyl groups in which the radical centers are on the terminal carbons are also preferred, eg methanediyl (methane); ethane-1,2-diyl (ethane); propane-1,3-diyl (propane); butane-1,4-diyl (butane) and the like (also referred to as alkylenes, intra defined).

"Alkyldiyl," by itself or as part of another substituent, refers to a divalent cyclic, linear, or branched, saturated or unsaturated hydrocarbon group having the stated number of carbon atoms (i.e., C1-C6 means 1 to 6 carbon atoms) derived from the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene, or alkyne, or from the removal of two hydrogen atoms from a single carbon atom of an alkane , alkene or original alkyne. The two monovalent radical centers or each valence of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methanediyl; ethyldiyls such as ethane-1,1-diyl, ethane-1,2-diyl, ethene-1,1-diyl, ethene-1,2-diyl; propyldiyls such as propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, propane-1,3-diyl, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl , prop-1 -ene-1, 1 -diyl, prop-1 -ene-1, 2- diyl, prop-2-ene-1,2-diyl, prop-1-ene-1,3-diyl, cycloprop-l-ene-1,2-diyl, cycloprop-2-ene-1,2-diyl, cycloprop-2-ene-1,1-diyl, prop-1-yne-1,3-diyl, etc.; butyldiyls such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,2-diyl, 2-ethylpropane-1,1 -diyl, 2-ethylpropane-1,2-diyl, cyclobutane-1,1-diyl; cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, but-1-ene-1,1-diyl, but-1-ene-1,2-diyl, but-1-ene-1,3- diyl, but-1-ene-1,4-diyl, 2- ethylprop-1-ene-1,1-diyl, 2- ethanylidenepropane-1,1-diyl, buta-

1,4-diyl, cyclobut-1-ene-1,2-diyl, cyclobut-1-ene-1,3-diyl, cyclobut-2-ene-1,2-diyl, cyclobuta-1,3-diene-1, 2-diyl, cyclobuta-1,3-diene-1,3-diyl, but-1-yne-1,3-diyl, but-1-yne-1,4-diyl, buta-1,3-diyne- 1,4-diyl, etc. and the like. When specific levels of saturation are desired, the alkanediyl, alkenediyl, and/or alkynediyl nomenclature is used. In a preferred embodiment, the alkanediyl group is C1-C6 alkane-diyl. Saturated acyclic alkanediyl groups in which the radical centers are on the terminal carbons are also preferred, e.g., methanediyl (methane), ethane-1,2-diyl (ethane), propane-1,3-diyl (propane), butane- 1,4-diyl(butane) and the like (also referred to as alkylenes, defined below).

"Alkylene", by itself or as part of another substituent, refers to a straight chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of two carbon atoms. terminals of the parent straight-chain alkane, alkene, or alkyne. The location of the double or triple bond, if present, in a particular alkylene is indicated in square brackets. Typical alkylene groups include, but are not limited to, methane; ethylenes such as ethane, ethene , ethyne; propylenes such as propane, prop[1]ene, propa[1,2]diene, prop[1]yne, etc.; butylenes such as butane, but[1]ene, but[2]ene, buta[ 1,3]diene, but[1]yne, but[2]yne, buta[1,3]diyne, etc. and the like When specific saturation levels are intended, the alkane, alkene and/or alkyne nomenclature is used In preferred embodiments, the alkylene group is C1-C6 or C1-C3 alkylene Saturated alkane groups are also preferred straight chain s, eg, methane, ethane, propane, butane, and the like.

"Heteroalkyl", "heteroalkanyl", "heteroalkenyl", "heteroalkynyl", "heteroalkyldiyl" and "heteroalkylene", by themselves or as part of another substituent, refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl or alkylene groups, respectively, in which one or more of the carbon atoms are each independently replaced by the same or a different heteroatom or heteroatomic group.Typical heteroatoms and/or heteroatomic groups that may replace atoms include, but are not limited to, -O-, -S-, -SO-, -NR'-, -PH-, -S(O)-, -S(0)2-, -S(O)NR '-, -S(0)2NR'- and the like, including combinations thereof in which each R' is independently hydrogen or (C1-C6)alkyl.

"Cycloalkyl" and "heterocycloalkyl," by themselves or as part of another substituent, refer to cyclic versions of "alkyl" and "heteroalkyl" groups, respectively. For heteroalkyl groups, a heteroatom can occupy the position that is bonded with the rest of the molecule.Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl, and the like.Typical heterocycloalkyl groups include, but are not limited to , tetrahydrofuranyl (eg, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyl (eg, piperidin-1-yl, piperidin-2-yl, etc.), morpholinyl (p .eg, morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl (eg, piperazin-1-yl, piperazin-2-yl, etc.), and the like.

"Acyclic heteroaromatic bridge" refers to a divalent bridge in which the backbone atoms are exclusively heteroatoms and/or heteroaromatic groups. Typical acyclic heteroaromatic bridges include, but are not limited to, -O-, -S-, -SO-, -NR'-, -PH-, -S(O)-, -S(0)2-, -S( O) NR'-, -S(0)2NR'- and the like, including combinations thereof in which each R' is independently hydrogen or (C1-C6)alkyl.

"Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a conjugated n-electron system. Specifically included in the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, s-indacene, indane, indene, naphthalene , octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyrantrene, rubycene, tetrahydronaphthalene, triphenylene, trinaphthalene and the like, as well as those various hydrated isomers thereof.

"Aryl", by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group having the stated number of atoms of carbon (ie, (C5-C15) means 5 to 15 carbon atoms) derived from the removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene , naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubycene, triphenylene, trinaphthalene and the like, as well as those various hydrated isomers thereof. In preferred embodiments, the aryl group is (C5-C15)aryl, with (C5-C10) being even more preferred. Particularly preferred aryls are cyclopentadienyl, phenyl and naphthyl.

"Arylaryl," by itself or as part of another substituent, refers to a monovalent hydrocarbon group derived by the removal of a hydrogen atom from a single carbon atom of a ring system in which two or more systems are directly joined. original aromatic ring systems identical or non-identical to each other by a single bond, wherein the number of said direct ring connections is one less than the number of original aromatic ring systems involved. Typical aryl groups include, but are not limited to, biphenyl, triphenyl, phenylnaphthyl, binaphthyl, biphenylnaphthyl, and the like. When the number of carbon atoms in an aryl aryl group is specified, the numbers refer to the carbon atoms that comprise each parent aromatic ring. For example, (C5-C15)arylaryl is an arylaryl group in which each aromatic ring comprises 5 to 15 carbon atoms, eg, biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parent aromatic ring system of an arylaryl group is independently a (C5-C15) aromatic, more preferably a (C5-C10) aromatic. Also preferred are aryl aryl groups in which all of the parent aromatic ring systems are identical, eg, biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

"Biaryl", by itself or as part of another substituent, refers to an arylaryl group having two identical parent aromatic systems directly linked to each other by a single bond. Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, bianthracyl, and the like. Preferably, the aromatic ring systems are (C5-C15) aromatic rings, more preferably (C5-C10) aromatic rings. A particularly preferred biaryl group is biphenyl.

"Arylalkyl", by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms attached to it is replaced. one carbon atom, typically a terminal or sp3 carbon atom, for an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2- naphthophenylethane-1-yl and the like. When specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, and/or arylalkynyl is used. In preferred embodiments, the arylalkyl group is (C6-C21)arylalkyl, eg, the alkanyl, alkenyl, or alkynyl moiety of the arylalkyl group is C1-C6 and the aryl moiety is C5-C15. In particularly preferred embodiments, the arylalkyl group is (C6-C13), eg, the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C3) and the aryl moiety is (C5-C10). "Parent heteroaromatic ring system" refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced by the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatomic groups to replace carbon atoms include, but are not limited to, N, NH, P, O, S, S(O), S(0)2, Si, etc. Specifically included in the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more of the rings is aromatic and one more of the rings is saturated or unsaturated such as, for example, benzodioxane, benzofuran, chroman , chromene, indole, indoline, xanthene, etc. Also included in the definition of "parent heteroaromatic ring system" are those recognized rings that include common substituents such as, for example, benzopyrone and 1-methyl-1,2,3,4-tetrazole. Typical parent heteroaromatic ring systems include, but are not limited to, acridine, benzimidazole, benzoisoxazole, benzodioxane, benzodioxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole, p-carboline, chroman, chromene, cinnoline , furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, 30 isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

"Heteroaryl," by itself or as part of another substituent, refers to a monovalent heteroaromatic group having the stated number of ring atoms (e.g., "5-14 members" means 5 to 14 ring atoms). ring) derived from the removal of a hydrogen atom from a single atom of a parent heteroaromatic ring system Typical heteroaryl groups include, but are not limited to, groups derived from acridine, benzimidazole, benzoisoxazole, benzodioxane, benzodiaxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole, p-carboline, chromane, chromene, cynoline, furan, imidazole, indazole, indole, indoline , indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole , pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, as well as the various hydrated isomers thereof. In preferred embodiments, the heteroaryl group is a 5-14 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.

"Heteroaryl-heteraryl", by itself or as part of another substituent, refers to a monovalent heteroaromatic group derived by the removal of a hydrogen atom from a single atom of a ring system in which two or more systems are directly joined. parent heteroaromatic ring systems identical or non-identical to each other by a single bond, wherein the number of said direct ring connections is one less than the number of parent heteroaromatic ring systems involved Typical heteroarylheteroaryl groups include, but are not limited to, bipyridyl , tripyridyl, pyridylpurinyl, bipurinyl, etc. When the number of atoms is specified, numbers refer to the number of atoms comprising each parent heteroaromatic ring system For example, 5-15 membered heteroarylheteroaryl is a heteroarylheteroaryl group in which each parent heteroaromatic ring system comprises 5 to 15 atoms, eg, bipyridyl, tripyridyl, etc. Pre Preferably, each parent heteroaromatic ring system is independently a 5-15 membered heteroaromatic, more preferably a 5-10 membered heteroaromatic. Heteroarylheteroaryl groups in which all the original heteroaromatic ring systems are identical are also preferred.

"Biheteroaryl", by itself or as part of another substituent, refers to a heteroarylheteroaryl group having two identical parent heteroaromatic ring systems directly linked to each other by a single bond. Typical biheteroaryl groups include, but are not limited to, bipyridyl, bipurinyl, biquinolinyl and the like.

Preferably, the heteroaromatic ring systems are 5-15 membered heteroaromatic rings, more preferably 5-10 membered heteroaromatic rings. "Heteroarylalkyl", by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom, typically a terminal or sp3 carbon atom, is replaced by a group heteroaryl. When specific alkyl moieties are intended, the nomenclature heteroarylalkyl, heteroarylalkenyl, and/or heteroarylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, eg, the alkanyl, alkenyl, or alkynyl moiety of heteroarylalkyl is (C1-C6)alkyl and the heteroaryl moiety is 5-15 membered heteroaryl. In particularly preferred embodiments, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, eg, the alkanyl, alkenyl or alkynyl moiety is (C1-15 C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

"Halogen" or "halide", by itself or as part of another substituent, unless otherwise stated, refers to fluorine, chlorine, bromine and iodine.

"Haloalkyl", by itself or as part of another substituent, refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen. Thus, the term "haloalkyl" is intended to include monohaloalkyls, dihaloalkyls, trihaloalkyl, etc. to perhaloalkyl.For example, the term "(C1-C2)haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl , perfluoroethyl, etc.

The groups defined above may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As examples, "alkyloxy" or "alkoxy" refers to a group of the formula -OR", "alkylamine" refers to a group of the formula -NHR" and "dialkylamine" refers to a group of the formula -NR"R" , wherein each R" is independently an alkyl. As another example, "haloalkoxy" or "haloalkyloxy" refers to a group of the formula -OR'", where R'" is a halogenoalkyl.

The present invention is also directed to methods or procedures for treating or preventing infections caused by a pathogen in the respiratory system such as, but not limited to: pneumonia, bacterial pneumonia, viral pneumonia, atypical pneumonia, graft-versus-host disease (GVHD), coronavirus disease 2019 (COVID-19), sepsis, Ebola, avian flu, smallpox, common flu, pancreatitis, a viral infection, or infections leading to acute respiratory distress syndrome (ARDS), acute respiratory syndrome severe (SARS), syndrome systemic inflammatory response (SIRS), or thrombocytopenia syndrome (SFTS), by administering to an individual in need thereof, an effective amount of any one of the compounds, compositions, or pharmaceutical compositions described herein.

In the present invention, the expression "respiratory system" or respiratory apparatus refers to the entire set of organs and structures possessed by living beings whose purpose is the exchange of gases with the environment.

Pharmaceutical compositions of the invention include a "therapeutically effective amount" or a "prophylactically effective amount" of one or more of the unsaturated analogs of docosanoic acid of the invention. A "therapeutically effective amount" refers to an effective amount, at dosages and for periods of time necessary, to achieve the desired therapeutic result, e.g., a reduction or prevention of effects associated with various disease states or conditions. . The therapeutically effective amount of an unsaturated analogue of docosanoic acid may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the therapeutic compound to elicit the desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by beneficial therapeutic effects.

A "prophylactically effective amount" refers to an amount effective, at dosages and over periods of time, necessary to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

Dosage regimens can be adjusted to provide the optimal desired response (eg, a therapeutic or prophylactic response). For example, a single bolus injection may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the mammalian subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of the dosage unit forms of the invention are dictated by and are directly dependent on (a) the unique characteristics of the unsaturated analogue of docosanoic acid and the particular therapeutic or prophylactic effect to be achieved and (b) the inherent limitations in the matter of combining said active compound for the treatment of sensitivity in individuals.

An exemplary non-limiting range for a therapeutically or prophylactically effective amount of an unsaturated analog of docosanoic acid of the invention is 0.01-20 mg/kg, more preferably 0.1-10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is further to be understood that, for any particular subject, issued dosage regimens should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth in herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

When the compounds of the present invention are administered as pharmaceuticals to humans and mammals, they may be procured per se or as a pharmaceutical composition containing, for example, from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient, i.e. at least one unsaturated analog of docosanoic acid, in combination with a pharmaceutically acceptable carrier.

In certain embodiments, the compounds of the present invention may contain one or more acidic functional groups and thus are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are, within within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable and effective benefit/risk ratio for their intended use of the compounds of the invention.

The term "salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. these salts they can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt so formed. These may include alkali and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see, eg, Berge SM, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:119).

The term "pharmaceutically acceptable esters" refers to the relatively non-toxic esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid or hydroxyl form with a suitable esterifying agent. Carboxylic acids can be converted to esters by treatment with an alcohol in the presence of a catalyst. The term is intended to further include lower hydrocarbon groups capable of solvating under physiological conditions, eg, alkyl esters, methyl, ethyl and propyl esters.

Wetting, emulsifying and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol , tartaric acid, phosphoric acid and the like.

The formulations of the present invention include those suitable for intravenous, oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a dosage form The only amount will generally be that amount of the compound that produces the therapeutic effect. Generally, by percentage, this amount will range from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, formulations are prepared by bringing a compound of the present invention into uniform and intimate association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), powders, granules, or as a solution or suspension in a liquid. aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as tablets (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus injection, electuary, or paste.

In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. and/or any of the following; fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as, for example, methyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; lubricants such as talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (eg gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agent or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes, and/or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of inhibiting compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, micro-emulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, forms of Liquid dosage form may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol 1,3-butylene glycol, oils (particularly cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, and mixtures thereof. They may also include anionic modified celluloses such as: microcrystalline cellulose, sodium carboxymethylcellulose, ethylhydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylmethylcellulose, ethylcellulose and/or methylcellulose, and a hydrophilic emulsifier.

Apart from inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or vehicles comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

Formulations of the present invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing those carriers known in the art to be appropriate.

Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required. Ointments, emulsions, oil-in-water emulsions, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the added advantage of providing a controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of said flux can be controlled by providing a rate controlling membrane or by dispersing the active compound in a polymeric matrix or gel.

Also contemplated as within the scope of this invention are ophthalmic formulations, ointments, powders, ocular solutions, and the like.

Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, emulsions, or sterile powders which may be reconstituted into solutions or dispersions. sterile injectables just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or thickening or suspending agents.

Examples of suitable aqueous and non-aqueous vehicles that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and through the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable dosage form can be caused by the inclusion of absorption retarding agents such as aluminum monostearate and gelatin.

In some cases, to prolong the effect of a drug, it is desirable to delay the absorption of the drug from a subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The absorption rate of the drug then depends on its dissolution rate which, in turn, may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Extended release injectable forms are made by forming microencapsulation matrices of the compounds in question in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(ortho-esters) and poly(anhydrides). Extended-release injectable formulations are also prepared by entrapping the drug in liposomes or micro-emulsions that are compatible with body tissue.

The preparations of the present invention can be obtained orally, nasally, parenterally, topically or rectally. They are of course procured in forms suitable for each route of administration. For example, they are administered in the form of tablets or capsule, by injection, inhalation (via an inhaler), eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topically by lotion or ointment and rectally by suppositories. Intravenous injection administration is preferred. The phrases "parenteral administration" and "parenterally administered," as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal injection. , intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal, and infusion.

The phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered," as used herein, mean the administration of a compound, drug, or other material other than directly into the nervous system. central, such that it enters the patient's system and thus undergoes metabolism and other similar processes, for example, subcutaneous administration.

These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including oral and nasal, such as by spray, rectal, intravaginal, parenteral, intracisternal, and topical, such as powders, ointments, or drops. including buccally and sublingually. Regardless of the route of administration selected, the compounds of the present invention that may be used in a suitable hydrated form and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional procedures known to those skilled in the art. . The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. patient.

The dosage level selected will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion of the compound being used, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts. A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may begin dosing the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of compound which is the lowest effective dose to produce a therapeutic effect. Said effective dose will generally depend on the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0. 01 to about 50 mg per kg per day, and even more preferably from about 0.1 to about 40 mg per kg per day. For example, between about 0.01 and 20 micrograms, between about 20 and 100 micrograms, and between about 10 and 200 micrograms of the compounds of the invention are administered per 20 g of subject weight.

If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.

The invention features an article of manufacture comprising packaging material and the formulation of at least one unsaturated analogue of docosanoic acid of the invention, comprised in the packaging material. This formulation comprises at least one unsaturated analog of docosanoic acid and the packaging material comprises a label or package insert indicating that the formulation can be administered to the subject to treat one or more conditions as described herein, in an amount, at a frequency and for a duration effective to treat or prevent said condition(s) mentioned throughout the specification. Suitable unsaturated analogs of docosanoic acid are described herein.

The present invention provides novel uses of compounds and compositions relating to mono-, di- and trihydroxyl unsaturated analogs of docosanoic acid. fundamentally characterized by having a hydroxyl group at C-14 of the carbon chain.

According to the present description, the use of a compound of the invention or of a pharmaceutical composition for the manufacture of a medicine or alternatively its use as a medicine, for the treatment of a disorder, disorder or disease described above, can obviously be understood as a method of treating such disorder, disorder or disease, comprising administering to a subject a therapeutically effective amount of said compound or pharmaceutical composition of the invention. In other words, the present invention also relates to a method of treating a disorder, disorder or disease comprising administering to a subject the compound of the invention in a therapeutically effective amount, or a pharmaceutical composition of the invention comprising the compound of the invention in a therapeutically effective amount.

DESCRIPTION OF THE FIGURES

Fig. 1. Shows the weight variation of the group of animals infected with SARS-CoV-2, treated or not with a compound of formula (I), the methyl ester of 7R,14S- maresin 1 (MaR1 ME) and Lipinova ^® (a composition comprising the compound of formula (IV), 14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid, in the triglyceride form, or 14-HDHA), compared to the untreated group uninoculated (Control). Thus, it can be seen that body weight loss decreases significantly in animals exposed to SARS-CoV-2 treated with MaR1 ME and Lipinova ^® . In the case of the groups treated with MaR1 ME, the improvement in weight loss is dose-dependent, with the highest dose of MaR1 ME leading to very little body weight loss of less than 5%.

Fig. 2. Shows the profile of the cytokine TNF-a obtained by qRT-PCR assay in the lung tissues of hamsters infected with SARS-CoV-2 treated and untreated at 4 dpi, 7 dpi and 14 dpi (n = 6 per day). Treatments started on the second day after infection. Fig. 3. Shows the effect produced by the treatment with MaR1 ME and Lipinova ^® of infected animals, finding that the viral load in the lungs is significantly reduced after a few days of treatment.

EXAMPLES

Example 1 Determination of the content of SPMs in plasma

Obtaining the plasma samples: For the present trial, blood was collected from (5) patients with COVID-19 and (5) healthy subjects. For this, 21-gauge butterfly needles were used to draw blood into a 10-ml syringe containing heparin (10 units/ml). The collected sample was then transferred to a 15 ml polypropylene tube and centrifuged for 20 minutes at 120G. The supernatant (plasma) was then collected with a Pasteur pipette and placed in another 15 ml polypropylene tube. The tube with the plasma was stored at -80 °C.

Processing prior to LC-MS/MS analysis: Plasma sample was thawed at room temperature, centrifuged at 1000G for 30 min before solid phase extraction. Internal standards (500 pg each) d4-PGE2, d5-LXA4, d4-LTB4, d8-5S-HETE, and d5-RvD2, representing each region in the chromatographic analysis, were added to the sample in 4V methanol. To induce protein precipitation, the samples were kept at -20 °C for 45 min. The supernatant was taken and a solid phase extraction was performed. The matrix-bound eicosanoids and SPMs were dried and suspended in a methanol/H20 mixture (1:1) to be injected into a SCI EX QTRAP 5500 hybrid triple quadrupole LC-MS/MS mass spectrometer system.

SPMs concentration (pg/mL) in human plasma samples from COVID-19 patients and healthy subjects (nd = not detected).

Table 1. Bioactive metabolome related to docosahexaenoic acid (DHA).

Table 2. Bioactive metabolome related to docosapentaenoic acid (EPA).

Table 3. Bioactive metabolome related to arachidonic acid (AA).

The analysis of the bioactive metabolome of Covid-19 patients shows a series of differences with respect to the metabolome of healthy people. In the case of the compounds of the present invention, represented by the compound of formula (I), 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (MaR1), it is surprisingly observed that and unlike healthy individuals, in Covid-19 patients this lipid mediator is not present in blood (plasma) or if it is, it does so at undetected concentrations.

In addition, marked decreases in the concentration of RvE1 (-45%), RvD2 (-32%), RvD4 (-75%), and PDX (-58%) in plasma are observed. These highly differentiated values between healthy people and Covid-19 patients indicate that these pro-resolution lipid mediators are relevant in this pathology. A decrease in the values of these lipid mediators in a subject is indicative of suffering from a disease caused by a pathogen in the respiratory system, while a patient suffering from one of the diseases described in the present invention whose levels of RvE1, RvD2, RvD4, PDX, and MaR1 increases over time will be indicative of patient improvement.

On the other hand, a substantial increase is observed in two pro-inflammatory lipid mediators, PGD2 (+436%), and LTB4 (+264%). Therefore, these lipid mediators are relevant in this pathology. Its decrease over time will indicate that the patient tends towards an optimal or healthy state, while its increase is indicative of a worsening of the patient. Example 2 Viruses

The SARS-CoV-2 virus was isolated from a nasopharyngeal aspirate sample of a patient with laboratory-confirmed COVID-19. The plaque-purified viral isolate was amplified by further passage in VeroE6 cells to obtain working virus stocks as previously described (Chan JF, Yip CC, To KK, et al. Improved molecular diagnosis of COVID-19 by the new highly sensitive real-time reverse transcription polymerase chain reaction assay specific for COVID-19-RdRp/Hel validated in vitro and with clinical samples J Clin Microbiol 2020 Mar 4 ).

Animal experiments.

Male LVG Golden Syrian hamsters (body weight 100-150 g, from Charles River, strain code 049) were kept in biosafety level 2 housing, and given access to a standard feed of pellets and water on demand. for 6-10 days prior to virus inoculation, which was performed in biosafety level 3 animal facilities. For this, phosphate buffered saline (PBS) was used to dilute the virus stocks to the desired concentration, and the inocula were readjusted to verify the administered dose. Dulbecco's modified Eagle's medium (DMEM) containing 105 plaque-forming units in 100 pl of SARS-CoV-2 was inoculated intranasally under intraperitoneal anesthesia of ketamine (200 mg/kg) and xylazine (10 mg/kg). Mock infected animals were challenged with 100 pl PBS. Throughout the experiment, animals were monitored twice daily for clinical signs of disease. Their body weight and survival were monitored for 14 days after inoculation.

Seventy-six (76) hamsters were inoculated with SARS-CoV-2 virus titration solution on day 0, and twelve (12) animals were mock-inoculated on the same day (Table 4). Body weight and clinical signs were evaluated daily, twice daily respectively, starting three days before inoculation (Day - 3). On the second day after inoculation, four (4) inoculated animals and three (3) sham-inoculated animals were sacrificed by intraperitoneal (ip) injection of pentobarbital at 200 mg/kg and appropriate tissues were collected (nasal turbinate, trachea, lungs, selected portion of the gastrointestinal tract) for viral load and histopathology. Blood profiles of selected cytokines/chemokines (TNF-a, IL-6, IL-1, IL-8, and MCP-1) and compounds herein were also measured. invention (methyl 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoate or MaR1 ME which is a compound of formula (I), and Lipinova®, which is a composition comprising 14S-hydroxy acid -4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid or 14-HDHA, which is a compound of formula (IV), in triglyceride form). The remaining inoculated animals (72) animals were separated into four (4) cohorts of eighteen (18) animals. Two cohorts were treated twice daily (ip) with MaR1 ME (dose 0.05 and 0.5 mg/kg), one cohort was treated twice daily (ip) with vehicle, and the remaining group was treated twice daily (gavage). with Lipinova®.

On day four, six (6) animals from each inoculated cohort (treated and untreated) and three (3) mock inoculated animals were sacrificed, appropriate tissues were collected for viral load and histopathology, and cytokine profiles were measured. / chemokines in blood. On the seventh day, six (6) animals from each inoculated cohort (treated and untreated) and three (3) mock inoculated animals were sacrificed, appropriate tissues were collected for viral load and histopathology, cytokine/chemokine profiles were measured in blood and SPMs.

On the fourteenth day, six (6) animals from each inoculated cohort (treated and untreated) and three (3) mock inoculated animals were sacrificed, appropriate tissues were collected for viral load and histopathology, cytokine profiles were measured/ blood chemokines and SPMs. Blood and tissues from major organs at necropsy were separated into two parts, one immediately fixed in 10% PBS-buffered formalin, and the other immediately frozen at −80 °C until use.

Table 4. General description of the animal test.

* Baseline lesion

Body weight variation The variation in body weight of the test animals of the group of animals infected with SARS-CoV-2, treated or not with a compound of formula (I), MaR1 ME and Lipinova® (composition comprising 14- HDHA, a compound of formula (IV), in the triglyceride form), and the results were compared with those of the uninoculated and untreated group (Control). Thus, animals inoculated with SARS-CoV-2 but not treated exhibited a progressive body weight loss of up to ~15% between days 1 and 5 post-injection (dpi), and then gradually regained their weight up to 14 dpi. . These animals developed lethargy, curly fur, a hunched posture, and rapid breathing as early as 2 dpi, and began to recover at 7 dpi. While in animals exposed to SARS-CoV-2 and treated with MaR1 ME and Lipinova®, it can be observed that body weight loss decreases significantly. In the case of the groups treated with MaR1 ME, the improvement in weight loss was dose-dependent, with the highest dose of MaR1 ME leading to the lowest body weight loss, which was less than 5%. None of the SARS-CoV-2-infected or sham-infected animals died. Histopathology and immunohistochemistry.

The tissue (nasal turbinate, trachea, lungs, selected portion of the gastrointestinal tract) was fixed in 4% paraformaldehyde and processed for paraffin embedding. The 4 pm sections were stained with hematoxylin and eosin for histopathological examinations. For immunohistochemistry, the SARS-CoV-2 N protein was detected using the monoclonal antibody (4D11) (Nicholls, M. et al. “Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS” PLoS Med., 3, e27, (2006)).

Cytokine/Chemokine Profile

Chemokine/cytokine profiling was performed in lung tissues and blood from virus-infected and sham-infected animals by qRT-PCR (Espitia CM, Zhao W, Saldarriaga O, et al. “Dúplex real-time reverse transcriptase PCR to determine cytokine mRNA expression in a hamster model of New World cutaneous leishmaniasis.” BMC Immunol 2010;11:31).

Both treatment with MaR1 ME and Lipinova® both have a significant impact on the profile of chemokines and cytokines in infected animals. Figure 2 specifically illustrates the increase in the profile of the cytokine TNF-a in the lungs of the group of animals infected with SARS-CoV-2, where the animals that have been treated in parallel with MaR1 ME and Lipinova® show levels of TNF -a significantly lower than untreated animals. Determination of viral load by real-time quantitative RT-PCR.

RNA was extracted from 140 µl of tissue homogenate using the QlAamp viral RNA mini kit (Qiagen), and eluted with 60 µl of water. The SARS-CoV-2 virus N gene was detected and quantified using TaqMan™ Fast Virus 1-Step Master Mix as described (Chu, KW et al. in “Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia.” Clin. Chem., doi: 10.1093/clinchem/hvaa029 (2020).

MaR1 ME and Lipinova® treatments have a significant impact on viral load in tissues. Figure 3 shows that in infected animals treated with MaR1 ME and Lipinova®, the viral load in the lungs is significantly reduced after a few days of treatment.

Claims

1.- An unsaturated analogue of docosanoic acid of formula (I):

(I)

where each of Pi and P2, individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

— C(0)R ^d , — C(0)OR ^d , — C(0)NR ^c R ^c , — C(NH)NR ^C R ^C , — C(NR ^a )NR ^c R ^c , — C( NOH)R ^a ,

— C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n OR ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in treating an infection caused by a pathogen in the respiratory system, where expressly excluded are: 7R, 14S-Dihydroxy-4Z,8E, 10E, 12Z, 16Z, 19Z-docosahexaenoic acid; 7S,14S-Dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid; and 7S, 14S-Dihydroxy-4Z, 8E, 10E, 12Z, 16Z, 19Z-docosahexaenoic acid, when the pathogen is not Covid-19.

2. An unsaturated analog of docosanoic acid of formula (I) according to claim 1, where Pi and P ₂ are both hydrogen atoms.

3. An unsaturated analog of docosanoic acid of formula (I) according to claim 1, where the double bonds of C-8 and C-10 are in the E configuration.

4 An unsaturated analog of docosanoic acid of formula (I) according to claim 1, where the C-14 hydroxyl has an S configuration.

5.- An unsaturated analogue of docosanoic acid of formula (II): as)

where each of Pi and P ₂ , individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

— C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n OR ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system.

6. An unsaturated analog of docosanoic acid of formula (II) according to claim

5, where Pi and P ₂ are both hydrogen atoms.

7. An unsaturated analogue of docosanoic acid of formula (II) according to claim

6, where the double bonds at positions C-5 and C-12 are each in the E configuration.

8. An unsaturated analogue of docosanoic acid of formula (II) according to claim

7, where the C-14 hydroxyl has an S configuration.

9.- An unsaturated analogue of docosanoic acid of formula (III):

(K!)

where each of Pi and P, individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

— C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n OR ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system, where 13R,14S-Dihydroxy-4Z,7Z,9E,11 E,16Z,19Z-docosahexaenoic acid is expressly excluded, when the pathogen is not Covid-19.

10. An unsaturated analog of docosanoic acid of formula (III) according to claim 9, where P and P are both hydrogen atoms.

11. An unsaturated analog of docosanoic acid of formula (III) according to claim 10, where Z is — C(0)0R ^d , where R ^d for Z is other than hydrogen.

12. An unsaturated analog of docosanoic acid of formula (III) according to claim 11, wherein the C-14 hydroxyl has an S configuration.

13.- An unsaturated analogue of docosanoic acid of formula (IV):

ÜV5

where Pi is a protecting group or a hydrogen atom; where is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^C R ^C , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

— C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C (0)] _n R ^d , —

[NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c or — [NR ^a C(NR ^a ) ] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system, where expressly excluded are: 14-Hydroxy-4Z,7Z, 10Z, 12Z, 16Z, 19Z-docosahexaenoic acid; 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid; Y

Ethyl 14-Hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoate, when the pathogen is not Covid-19.

14. An unsaturated analog of docosanoic acid of formula (IV) according to claim 13, where Pi is a hydrogen atom.

15. An unsaturated analog of docosanoic acid of formula (IV) according to claim 14, where Z is — C(0)0R ^d , where R ^d for Z is hydrogen.

16.- An unsaturated analog of docosanoic acid of formula (IV) according to claim 15, where the double bond in the C-12 position is in the E configuration.

17. An unsaturated analog of docosanoic acid of formula (IV) according to claim 16, wherein the C-14 hydroxyl has an S configuration.

18.- An unsaturated analogue of docosanoic acid of formula (V):

(Saw

where each of Pi, P ₂ and P ₃ , individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

— C(NOH)NR ^c R ^c , — OC(0)R ^d , — OC(0)OR ^d , — OC(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n OR ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system

19. An unsaturated analogue of docosanoic acid of formula (V) according to claim 18, where Pi, P ₂ and P ₃ are all hydrogen atoms.

20. An unsaturated analog of docosanoic acid of formula (V) according to claim 19, where Z is — C(0)OR ^d .

21. An unsaturated analog of docosanoic acid of formula (V) according to claim 20, wherein the C-14 hydroxyl has an S configuration.

where each of Pi and P2, individually, is a protecting group or a hydrogen atom; where is a double bond; where Z is — C(0)OR ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^C R ^C , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ OR ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — OS(0)R ^d , — OS(0) ₂ R ^d , — OS(0) ₂ OR ^d , — OS(0) ₂ NR ^c R ^c ,

23. An unsaturated analog of docosanoic acid of formula (VI) according to claim 22, where Pi and P are both hydrogen atoms.

24. An unsaturated analog of docosanoic acid of formula (VI) according to claim 23, where Z is — C(0)0R ^d .

25. An unsaturated analog of docosanoic acid of formula (VI) according to claim 24, wherein the C-14 hydroxyl has an S configuration.

26.- An unsaturated analogue of docosanoic acid of formula (Vil):

where each of Pi and P, individually, is a protecting group or a hydrogen atom; where = is a double bond; where Z is — C(0)0R ^d , — C(0)NR ^c R ^c , — C(0)H, — C(NH)NR ^C R ^C , — C(S)H, — C(S) OR ^d , — C(S)NR ^c R ^c , or — CN; where each R ^a is independently selected from hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; where each R ^c , is independently a protecting group or R ^a , or, alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5 to 8 membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different further heteroatoms and which may optionally be substituted by one or more of the same or different R ^a or suitably R ^b groups; where each R ^b is independently selected from =0, — OR ^d , (C1-C3)haloalkyloxy, — OCF ₃ , =S, — SR ^d , =NR ^d , =NOR ^d , — NR ^C R ^C , halogen, — CF ₃ , — CN, — NC, — OCN, — SCN, —NO, — N0 ₂ , =N ₂ , — N ₃ , — S(0)R ^d , — S(0) ₂ R ^d , — S (0) ₂ 0R ^d , — S(0)NR ^c R ^c , — S(0) ₂ NR ^C R ^c , — 0S(0)R ^d , — 0S(0) ₂ R ^d , — 0S(0) ₂ 0R ^d , — 0S(0) ₂ NR ^c R ^c ,

— C(NOH)NR ^c R ^c , — 0C(0)R ^d , — 0C(0)0R ^d , — 0C(0)NR ^c R ^c , — OC(NH)NR ^c R ^c , — OC(NR ^a )NR ^c R ^c , — [NHC(0)] _n R ^d , — [NR ^a C(0)] _n R ^d , — [NHC(0)] _n 0R ^d , — [NR ^a C(0) ] _n R ^d , — [NHC(0)] _n NR ^c R ^c , — [NR ^a C(0)0] _n NR ^c R ^c , — [NHC(NH)] _n NR ^c R ^c o — [NR ^a C(NR ^a )] _n NR ^c R ^c ; each n, independently, is a number selected from 0 to 3; each R ^d , independently, is a protecting group or R ^a ; or a pharmaceutically acceptable salt, tautomer and/or solvate thereof; for use in the treatment of an infection caused by a pathogen in the respiratory system, where 7, 14-Dihydroxy-8E,10E,12Z,16Z,19Z-eicosapentaenoic acid is expressly excluded, when the pathogen is not Covid-19 .

27. An unsaturated analog of docosanoic acid of formula (VII) according to claim 26, where Pi and P ₂ are both hydrogen atoms.

28. An unsaturated analog of docosanoic acid of formula (Vil) according to claim 27, where Z is — C(0)OR ^d .

29.- An unsaturated analog of docosanoic acid of formula (Vil) according to claim 28, where the C-14 hydroxyl has an S configuration.

30. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 29, and a pharmaceutically acceptable carrier, for use in the treatment of an infection caused by a pathogen in the respiratory system.

31. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 29, and the compounds 17-hydroxy-4Z,7Z, 10Z, 13Z, 15E, 19Z-docosahexaenoic acid ("17-HDHA") , and 18-hydroxy-acid

5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid (“18-HEPE”) for use in treating an infection caused by a pathogen in the respiratory system.

32.- A pharmaceutical composition according to claim 31, wherein the compound according to any one of claims 1 to 29, and the 17-HDHA and 18-HEPE compounds are in free form, such as esters, ethyl esters, triglycerides , diglycerides, monoglycerides, sphingolipids, phospholipids, or as mixtures thereof.

33.- A pharmaceutical composition according to any one of claims 30 to 32, wherein the infection caused by a pathogen in the respiratory system is selected from: pneumonia, bacterial pneumonia, viral pneumonia, atypical pneumonia, graft-versus-host disease (GVHD ), COVID-19, Covid-19 viral load reduction, SARS-CoV1, sepsis, Ebola, avian flu, smallpox, or common flu.

34. A pharmaceutical composition according to claim 33, wherein the infection caused by a pathogen in the respiratory system is selected from viral pneumonia, bacterial pneumonia, or atypical pneumonia.

35. A pharmaceutical composition according to claim 34, wherein the infection caused by a pathogen in the respiratory system is a viral pneumonia.

36.- A nutritional supplement or food-medication comprising at least one compound according to any one of claims 1 to 29, and the compounds 17-HDHA, and 18-HEPE, for use in improving the health of a patient suffering from an infection caused by a pathogen in the respiratory system.

37.- A nutritional supplement or food-medication comprising at least one compound according to any one of claims 1 to 29, and the compounds 17-HDHA, and 18-HEPE, for use in reducing the viral load of a patient.

38.- A nutritional supplement or food-medication according to any one of claims 36 to 37, where the compounds are in free form, ethyl esters, triglycerides, diglycerides, monoglycerides, sphingolipids, phospholipids or as mixtures thereof .

39.- A nutritional supplement or a food-medication according to any one of claims 36 to 38, where the pathogen is Covid-19. 40.- A method of diagnosis and/or monitoring of the condition of a patient suffering from a disease caused by the presence of a pathogen in the respiratory system based on the identification and quantification of the concentration of pro-resolving lipid mediators in the blood, plasma, and/or serum of said patient, which are relevant in said disease.

41. A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, wherein the relevant lipid mediators are RvE1, RvD2, RvD4, MaR1, and PDX.

42.- A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, where it is determined if a subject suffers from any of the pathologies described in the present invention when a decrease of at least 30% is observed, With respect to a healthy individual, the concentration in blood, plasma and/or serum of each of the following pro-resolution mediators RvE1, RvD2, RvD4, MaR1, and PDX.

43.- A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, wherein the relevant pro-resolution lipid mediators are RvE1, RvD2, RvD4, MaR1 and PDX, and the pro-inflammatory lipid mediators formed are PGD2 and LTB4.

44. A method for diagnosing and/or monitoring the condition of a patient according to claim 40, wherein the increase in the pro-inflammatory mediator LTB4 is at least 100%, compared to a healthy individual.

45. A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, wherein the measurement of the concentration values of the pro-resolution mediators is carried out in plasma.

46. A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, wherein the measurement of the concentration values of the pro-resolution mediators is performed in serum.

47. A method of diagnosis and/or monitoring of the condition of a patient according to claim 46, wherein the blood sample is treated with an adenosine inhibitor selected from: adenosine deaminase (ADA), caffeine, 8-(3-chlorostyril )caffeine, 2- phenylaminoadenosine, 2-p-2-carboxyethylphenylamino-5'-N-ethylcarboxamido-adenosine, 5-N- ethylcarboxamido-adenosine, 5'-N-cyclopropyladenosine, 5'N-methylcarboxamidoadenosine, PD-1259444, 1 ,3-dipropyl-phenylxanthine, or 4-{2-[7-amino-2- (2-furyl)[1 , 2 , 4]-tri azole o[2 , 3-a]-[ 1 ,3,5 ]-triazin-5-ylamino]ethyl}phenol (ZM 241385).

48.- A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, where the disease caused by the presence of a pathogen in the respiratory system is selected from: pneumonia, bacterial pneumonia, viral pneumonia, or atypical pneumonia .

49. A method of diagnosis and/or monitoring of the condition of a patient according to claim 48, wherein the disease caused by the presence of a pathogen in the respiratory system is viral pneumonia.

50.- A method of diagnosis and/or monitoring of the condition of a patient according to claim 40, where the disease caused by the presence of a pathogen in the respiratory system is selected from COVID-19, SARS-CoV1, sepsis, Ebola , bird flu, smallpox, or common flu.